A continued and emerging threat to human health are multi-drug resistant bacterial infections. Among these threats, carbapenemase producing strains of Klebsiella spp has been recognized by the World Health Organization and the Centers for Disease Control has a global threat to human health particularly in the hospital setting. Clinically these infections often appear to be opportunistic infections affecting patients with co-morbidities such as immunosuppressive drugs, poor performance status, mechanical ventilation, and kidney disease. In addition, hematologic malignancies and solid organ and stem cell transplant recipients are at risk. Recently hyervirulent strains with mucoid capsule have been reported but carriage rates in areas of Asia can approach 5% in stool, which far exceeds the rate of clinical infection, suggesting host factors are important. Pulmonary inoculation of the non-mucoid ST258C4 strain was avirulent in WT mice as well as Rag-/- mice which lack T and B cells. In contrast Rag2, Il2rg -/- which additionally lack NK cells and innate lymphoid cells, were susceptible to infection and had mortality, which was associated bacterial dissemination. Single cell RNAseq of lung tissue demonstrated that NK cells and group 3 innate lymphoid cells were associated with bacterial clearance. In preliminary studies, only dual antagonism of both NK cells and group 3 ILCs resulted in ST258 infection suggesting these two cell populations are key to host defense against this organism. As IL-22:Fc is clinical trial for gut graft versus host disease and diabetic foot ulcers, we investigated if systemic IL-22:Fc administration could be used as immunotherapy. Preliminary studies show that IL-22:Fc can substantially reduce bacterial burdens in mice susceptible Rag2-/-, Il2rg -/- mice. To examine if these cellular responses were perturbed by clinically relevant immunosuppression, we administered FK506, which is used in solid organ transplant, to mice. FK506 treatment increased susceptibility to infection and reduced IFNg, Il17a, and Il22 in the lung. Thus, we have developed genetic and pharmacological models that allow us to propose the following testable hypothesis: ST258 C4 infection requires NK cells and group 3 ILC cells for clearance and these populations are inhibited by calcineurin inhibition. Moreover we hypothesize that cytokine based immunotherapy can be developed to augment endogenous host responses to clear this infection. We will test these hypotheses with the following specific Aims using both non-mucoid (C4) as well as hypermucoid strains of KPC: Specific Aim 1. Test the prediction that both NK cells and group 3 innate lymphoid cells are required for lung mucosal immunity against Kpc infection. Specific Aim 2. Develop a clinically and pharmacologically relevant model of Kpc infection. Specific Aim 3. Test the prediction that systemic or local immunotherapy is effective in controlling Kpc infection.